Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
  • A61L24/0047—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
  • A61L24/0073—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material with a macromolecular matrix
  • A61L24/0084—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material with a macromolecular matrix containing fillers of phosphorus-containing inorganic compounds, e.g. apatite
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
  • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
  • A61F2/02—Prostheses implantable into the body
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L24/00—Surgical adhesives or cements; Adhesives for colostomy devices
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
  • A61L27/40—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material
  • A61L27/44—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix
  • A61L27/46—Composite materials, i.e. containing one material dispersed in a matrix of the same or different material having a macromolecular matrix with phosphorus-containing inorganic fillers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
  • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
  • A61F2/02—Prostheses implantable into the body
  • A61F2/28—Bones
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
  • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
  • A61F2/02—Prostheses implantable into the body
  • A61F2/30—Joints
  • A61F2002/30001—Additional features of subject-matter classified in A61F2/28, A61F2/30 and subgroups thereof
  • A61F2002/30003—Material related properties of the prosthesis or of a coating on the prosthesis
  • A61F2002/3006—Properties of materials and coating materials
  • A61F2002/30062—(bio)absorbable, biodegradable, bioerodable, (bio)resorbable, resorptive
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
  • A61F2210/00—Particular material properties of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof
  • A61F2210/0004—Particular material properties of prostheses classified in groups A61F2/00 - A61F2/26 or A61F2/82 or A61F9/00 or A61F11/00 or subgroups thereof bioabsorbable
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
  • A61F2310/00—Prostheses classified in A61F2/28 or A61F2/30 - A61F2/44 being constructed from or coated with a particular material
  • A61F2310/00005—The prosthesis being constructed from a particular material
  • A61F2310/00179—Ceramics or ceramic-like structures
  • A61F2310/00293—Ceramics or ceramic-like structures containing a phosphorus-containing compound, e.g. apatite
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L2430/00—Materials or treatment for tissue regeneration
  • A61L2430/02—Materials or treatment for tissue regeneration for reconstruction of bones; weight-bearing implants

Definitions

• This invention relates to an improved composite material which may be used with advantage as a material for bone replacement or for joining bones and for implanting prosthesis material in living bone tissue. More particularly, the invention relates to the combination of known body-compatible ceramic materials, more particularly corresponding bioactive materials based on calcium phosphate, together with selected oligoesters which are also compatible with the body and which can be resorbed by the human and animal body.
• Ceramic materials having different resorption rates based on calcium phosphates more particularly tricalcium phosphate "TCP” and also pentacalcium hydroxide triphosphate ("hydroxyl apatite”), are now available for surgical use, particularly in sintered form.
• the sintered materials are distinguished by large apatite crystals and, in some cases, by additional fusion of the individual particles into a relatively large composite. The corresponding materials thus show increased resistance in biological medium.
• the ceramics differ in their porosity or density according to the particular production process used and the sintering temperature applied and contain both micropores (in the range from 1 ⁇ m up to about 100 ⁇ m in size) and larger macropores.
• a comparatively fine-particle to granular material of the type in question is used--for example in the maxillary region for restoring bone sections which have retained their continuity--by separating the gums from the bone and forming a cavity which is filled to the required extent with pelletized and/or granulated replacement material based on calcium phosphate.
• the opened periodontal pocket is then stitched and holds the filler in the required place.
• the free-flowing, fine-particle ceramic material has no dimensional stability of its own, but instead adapts itself to the predetermined shape of the tissue pocket formed. Shifting of the pocket filling can occur at a later stage before the replacement material has been adequately stabilized by new bone tissue growing in. On the other hand, if the suture is involuntarily opened, partial loss of the filling introduced can occur.
• this organic phase examples include polyesters of glycolic acid, lactic acid, polyamides of ⁇ -aminoacids, unmodified or modified natural polymers, such as gelatine or starch, triglycerides of higher alkane carboxylic acids or esters of polyhydroxy compounds and polymethyl methacrylate and polycyanoacrylate.
• the corresponding hard shaped structures are made in particular by impregnating the porous ceramic material with the polymer-forming monomer and then polymerizing the organic starting components in situ in the presence of the ceramic material.
• the invention seeks to provide improved composite materials of the described type which guarantee both easier handling and also rapid and safe "growing-in” of the fine-particle ceramic material introduced in direct contact with intact bone tissue.
• the problem addressed by the invention is solved by the use--together with the ceramic material--of selected oligomeric and/or polymeric polyester compounds which are compatible with the body and, in particular, can even be resorbed in the living organism and do not disturb the desired substitution process at the bone through unwanted secondary reactions, but instead--in one preferred embodiment--actually stimulate the substitution process and, in particular, are also capable of facilitating the shaping of the replacement material during the operation and of improving the dimensional accuracy of the implantate, particularly in the critical transition phase before adequate stabilization by the body's own bone tissue.
• One of the objects of the invention in this regard is to enable composite materials of the described type to be reproducibly obtained in any quantities and in the same, predeterminable quality, the materials in turn being distinguished by optimal tissue compatibility and being obtainable by methods in which no auxiliary chemicals foreign to the body are used.
• the present invention relates to at least partly resorbable materials for replacing and/or joining bones and to auxiliaries for implanting prosthesis material in living bone tissue, containing as essential components body-compatible ceramic materials in admixture with body-resorbable oligomers and/or polymers of lower hydroxycarboxylic acids, more particularly glycolic acid and/or lactic acid (hereinafter referred to as the "resin component"), the invention being characterized in that the resin component is produced using molecular-weight-regulating co-reactants from the class of mono- or polyfunctional carboxylic acids or corresponding alcohols and is substantially freed from free carboxyl groups.
• the resin component is produced using molecular-weight-regulating co-reactants from the class of mono- or polyfunctional carboxylic acids or corresponding alcohols and is substantially freed from free carboxyl groups.
• a combination of elements for defining the resin component of the described composite materials is thus essential to the invention.
• This resin component is preferably synthesized from glycolic acid and/or lactic acid units linked in the manner of polyesters.
• the co-use of selected co-reactants makes it possible in known manner to establish the average molecular weight which is a determining factor for the period of survival of the resin component in the metabolism of the living organism.
• the invention presupposes the use of resin components of the described type which have been substantially freed from free carboxyl groups. This is an important element for the compatibility of the resin components used in accordance with the invention with the body and, in particular, with the tissue.
• the molecular-weight-regulating co-reactants particular significance is attributed in one preferred embodiment of the invention to glycerol or selected glycerol partial esters, as will be described in more detail hereinafter.
• Corresponding oligomers and/or polymers having an average molecular weight in the range from about 200 to 1500 and preferably in the range from about 300 to 1000 are particularly suitable for this application.
• the preferred polyester oligomers are formed from monohydroxycarboxylic acids which preferably contain 2 to 10 and, more preferably, 2 to 6 carbon atoms. Polyester oligomers of glycolic acid, lactic acid, hydroxypropionic acid, hydroxybutyric acid and/or hydroxybenzoic acid are mentioned in particular.
• the most important hydroxycarboxylic acids in practice for the synthesis of the viscous to solid polymer components in question are glycolic acid and/or lactic acid.
• these waxes and corresponding compounds of even higher molecular weight which hitherto have mainly been proposed for the mechanical staunching of blood on bone, may advantageously be used in combination with mineral bone substitutes, more particularly of the type mentioned at the beginning.
• mineral bone substitutes more particularly of the type mentioned at the beginning.
• solid oligomers and/or polymers of the type mentioned are mixed with the fine-particle inorganic bone substitute in such quantities that the organic phase is present as the closed phase in the composite material
• the invention provides a formable and, if desired, dimensionally stable material which may be combined as an implantate in any desired spatial form with the body's own bone tissue.
• the organic polyester phase is not only physiologically safe, it is also resorbed in the manner described in applicants' earlier patent applications cited above without any toxic degradation products being formed.
• the body's own bone substance is built up and the degradation-resistant inorganic particles are incorporated in the new tissue formed. It has been found in this regard that the co-use of the selected hydroxycarboxylic acid polyester materials according to the invention can even specifically stimulate the regeneration of bone tissue having the desired structure. It is clear that operations using bone substitutes based on calcium phosphate can be improved in many respects by the use of the composite material according to the invention.
• the disclosures of applicants' earlier applications cited above apply equally to the organic polyester phase of the composite materials according to the invention, but with the proviso that the average molecular weight is in a broader range in their case, typically in the range from about 200 to 10,000 and preferably in the range from about 300 to 5,000 g/mol.
• Particularly important hydroxycarboxylic acids for forming the polyester oligomer segments are the already mentioned glycolic acid, the isomeric lactic acids, the optionally isomeric ⁇ - or ⁇ -hydroxypropionic acids, the optionally isomeric ⁇ -, ⁇ - or ⁇ -hydroxybutyric acids, o-hydroxybenzoic acid (salicylic acid), m-hydroxybenzoic acid and/or p-hydroxybenzoic acid (anisic acid).
• Certain isomers of the acids mentioned and also mixtures thereof may be used.
• the degradation rate of the wax by the body's own degradation reactions can be influenced to a considerable extent by using mixtures of different hydroxycarboxylic acids and, more particularly, by the use of glycolic acid and lactic acid together.
• High polymers of the type described above and their use in the medical field are known. They typically have fiber properties. Their compatibility and degradability have been studied in detail. For example, synthetic fibrous materials based on polyglycolic acid and polylactic acid which can be resorbed in the organism are known, cf. for example U.S. Pat. Nos. 3,297,033; 3,422,871; 3,626,948; 2,668,162; 2,676,945 and 2,703,316. Further literature references on the use of high polymers such as these can be found in the above-cited DE-OS 32 29 540.
• Monofunctional and/or polyfunctional alcohols or corresponding carboxylic acids are used as co-reactants in the preparation of the reaction product in order reproducibly to establish the particular degree of oligomerization and, hence, the required viscous to solid consistency of the reaction product.
• Suitable co-reactants and, in particular, examples of the important class of alcoholic co-reactants are again described in detail in the earlier applications cited above.
• Particular significance may be attributed in this regard to glycerol which may be used to optimize the tissue compatibility of the viscous to solid organic phase, as described in earlier application P 37 16 302.7 (D 7890).
• significance is attributed to partial esters of glycerol with, in particular, alcohols containing 12 to 18 carbon atoms.
• the wax-like material is freed from its content of unreacted starting components to such an extent that the content of unreacted hydroxycarboxylic acids is reduced to residual contents below 0.5% by weight and preferably to residual contents below about 0.2% by weight.
• the waxes used may contain residual contents of unreacted hydroxycarboxylic acids of or below 0.1% by weight.
• the removal of unreacted components or reaction products of undesirably low molecular weight from the oligomers initially formed may readily be achieved as follows: the educt initially formed is mixed with a water-miscible organic solvent, for example with acetone, methanol or ethanol or the like, and the suspension formed is subsequently introduced into a solvent which does not dissolve the desired oligomer fractions, but is an adequate solvent for unreacted components or reaction products of low molecular weight. Isopropanol has proved to be a particularly suitable precipitation medium for this second stage of the process.
• the solid suspension formed is then introduced into several times, for example 7 to 12 times, its volume of isopropanol and filtered off.
• the liquid phase is filtered under suction, washed, best with isopropanol, and dried.
• the oligomerization product initially formed is freed from free carboxyl groups in a totally different way.
• the free carboxyl groups are neutralized with suitable salt-forming, body-compatible cations, including above all alkali metals and/or alkaline earth metals, more particularly calcium and magnesium and, if desired, even aluminium. Relevant particulars can be found in applicants' above-cited earlier application P 38 25 211.2 (D 8293).
• suitable ceramic materials based on calcium phosphate and their chemical definition are concerned, reference is made to the publication by Fischer-Brandies et al which was cited at the beginning.
• the preferred ceramic material is sufficiently purified hydroxyl apatite and/or tricalcium phosphate.
• Other ions may be taken up into the crystal lattice in exchange, as mentioned in the cited literature reference.
• Sintered and, if desired, microporous and/or macroporous material or mixtures of such materials may be used.
• the new composite material contains powder-form and/or granulated ceramic materials based on calcium phosphate in intimate admixture with the organic phase, the inorganic, fine-particle material being present as disperse filler phase in hydroxycarboxylic acid oligomer or polymer which surrounds the disperse filler as continuous or closed phase.
• the organic phase is used in such a limited quantity that the composite material basically retains a granular or fine-particle character, although cores of inorganic material of the described type are surrounded and--in the case of porous inorganic materials--may even be at least partly permeated by the organic component.
• the first embodiment just described with the resin component as the continuous phase containing disperse ceramic particles may be in the form of a kneadable mass of which the kneadability is established if desired by the application of moderately elevated temperatures, although a dimensionally stable, solid mass is present at room temperature and preferably also at body temperature.
• this embodiment also encompasses materials which may be shaped by machining, i.e. by cutting, milling and the like.
• the second of the embodiments just described is a disperse bone substitute material in which the resin component is present at least as a coating of the individual particles, but if desired may even be absorbed into the interior of the individual particles.
• the sealing and/or filling of the porous structure of the inorganic material is the critical factor. On the one hand, it prevents unwanted residues of secretion and/or blood being trapped in the region of the wound, on the other hand the function of the resin component in stimulating bone regeneration is also in evidence in this form.
• powder-form calcium phosphate may be the sole ceramic material, in which case a range of about 100 to 200 ⁇ m may be regarded as the upper limit to the particle size of the powder-form materials.
• Bone-like, solid substitute materials of this type are formed in particular when the content of ceramic powder in these materials is at least about 30% by weight, preferably of the order of 40 to 80% by weight and, more preferably, in the range from about 40 to 65% by weight.
• the composite materials according to the invention contain the ceramic materials in granular form
• the preferred particle diameter of the granules is in the range from about 0.1 to 3 mm, preferably in the range from about 0.1 to 2 mm and more preferably in the range from about 0.2 to 1 mm.
• the preferred granule content is in the range from about 20 to 70% by weight and preferably in the range from about 20 to 60% by weight, although particular significance can be attributed to the range from about 25 to 50% by weight. All the percentages by weight mentioned are based on the total weight of the composite material according to the invention.
• the ceramic materials are present in an at least partly bimodal particle size distribution, mixtures of powder and granules being particularly suitable.
• other combinations are also possible, including for example the use of a mixture of granules of different size.
• One particularly preferred embodiment of the invention is characterized by the use of resin components based on the lower hydroxycarboxylic acids, more particularly glycolic and/or lactic acid, which have been prepared by condensation of monomeric starting elements in the absence of catalysts. It is known that this autocondensation of glycolic acid and lactic acid takes place under the effect of the carboxylic acid groups of the starting material which catalyze the esterification reaction. In this case, too, the reaction is carried out in the presence of the co-reactants regulating the desired molecular weight, more particularly in the presence of glycerol. The elimination of free carboxyl groups from the condensate in a final step, more particularly by salt formation with, for example, calcium and/or magnesium, is particularly important in these embodiments.
• the polycondensation of the resin component may be carried out in known manner initially under normal pressure with removal of the water of reaction formed and, if desired, under an increasing vacuum in later stages of the polycondensation reaction.
• the resin components may be mixed with the powder-form and/or granular ceramic materials in known manner. It is preferred in this regard to use the resin components in molten form. It can be of advantage, particularly where limited quantities of the resin component are incorporated in comparatively large quantities of the ceramic materials, to use inert auxiliary solvents for mixing the components, the solvents being removed on completion of mixing.
• Preferred solvents are solvents of sufficiently high volatility, such as acetone, readily volatile alcohols, esters and the like.
• Glycolic acid and glycerol are introduced into a three-necked flask equipped with a stirrer and distillation bridge. After blanketing with nitrogen, the contents of the flask are heated to 150° C. and the reaction is continued for 3 to 5 hours until no more water of reaction is eliminated. The flask is then carefully evacuated to 10 torr at a temperature of 150° C. After another 2 hours under these conditions, the reaction mixture is cooled to 100° C., the vacuum is eliminated and the product is neutralized as described in 2. below and packed in containers while still hot.
• Lactide (L(-)-Lactid N, a product of B ohringer Ingelheim) and glycerol were introduced into a standard laboratory reactor and heated with stirring under nitrogen over a period of 1 hour to a temperature of 195° C. The mixture was then left to react for three hours at 195° C. and, after neutralization as described in 2., was packed in containers while still hot.
• An Sn(II) chloride solution in ether was added as catalyst (7 ml of a solution of 2.5 g SnCl 2 in 1000 ml ether for the reaction of 3 mol lactide with 1 mol glycerol).
• the free acid (glycolic acid/lactic acid) content of the resins described in 1. was determined by titration.
• the free acid was neutralized by addition of an equimolar quantity of CaCO 3 and intensive mixing.
• Hydroxyl apatite was added to a melt of the neutralized resins with stirring at temperatures of 120° C. (low filling) to 160° C. (high filling), followed by intensive mixing for 15 minutes.
• the resins proved difficult to fill with more than 60% hydroxyl apatite.
• the resin was dissolved in acetone (1:1), filled with hydroxyl apatite while stirring and the solvent was subsequently evaporated.
• Shore A hardness was determined in accordance with DIN 53505, ASTM D 2240 (spike penetration depth) using the Zwick apparatus.
• Viscosity was determined with the following instrument: Epprecht type TVB torsional viscosimeter, measuring element 4, at 200 r.p.m./70° C. (heated samples).

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• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Life Sciences & Earth Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Engineering & Computer Science (AREA)
• Epidemiology (AREA)
• Composite Materials (AREA)
• Materials Engineering (AREA)
• Inorganic Chemistry (AREA)
• Oral & Maxillofacial Surgery (AREA)
• Transplantation (AREA)
• Surgery (AREA)
• Medicinal Chemistry (AREA)
• Dermatology (AREA)
• Cardiology (AREA)
• Biomedical Technology (AREA)
• Heart & Thoracic Surgery (AREA)
• Vascular Medicine (AREA)
• Orthopedic Medicine & Surgery (AREA)
• Materials For Medical Uses (AREA)
• Prostheses (AREA)

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Cited By (43)

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• 1988
  • 1988-08-09 DE DE3826915A patent/DE3826915A1/de not_active Withdrawn
• 1989
  • 1989-07-31 KR KR1019900700739A patent/KR0134223B1/ko not_active IP Right Cessation
  • 1989-07-31 EP EP89908425A patent/EP0428554B1/de not_active Expired - Lifetime
  • 1989-07-31 JP JP1507789A patent/JP2786495B2/ja not_active Expired - Fee Related
  • 1989-07-31 DE DE8989908425T patent/DE58904522D1/de not_active Expired - Lifetime
  • 1989-07-31 WO PCT/EP1989/000893 patent/WO1990001342A1/de active IP Right Grant
  • 1989-07-31 BR BR898907595A patent/BR8907595A/pt not_active Application Discontinuation
  • 1989-07-31 AU AU39724/89A patent/AU627209B2/en not_active Ceased
• 1991
  • 1991-01-31 NO NO910375A patent/NO178216C/no unknown
  • 1991-02-07 FI FI910600A patent/FI97331C/fi not_active IP Right Cessation
  • 1991-02-08 DK DK022191A patent/DK170017B1/da not_active IP Right Cessation
• 1994
  • 1994-11-04 US US08/334,633 patent/US5552454A/en not_active Expired - Lifetime

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